ABSTRACT Short gut syndrome (SGS) results from the surgical removal of a significant length of small intestine required to treat multiple conditions in adults and children. In children, the mortality associated with SGS is ~25%, making it one of the most lethal conditions in infancy and childhood. After surgery, remodeling of the remaining bowel segment can occur to reach a state more favorable to absorptive function and survival. Despite the importance of the lymphatic vasculature in fat absorption, little is known about how lymphatic transport is affected in SGS. Our preliminary data suggest that lymphatic vessel integrity is compromised in SGS. Since lymphatics are centrally involved in transport of fat nutrients into the host, it is relevant to consider how lymphatic vessel changes in SGS might affect the subject's health. The development of fatty liver progressing to liver failure, or intestinal failure-associated liver disease (IFALD), is the major morbidity in SGS patients that survive bowel resection. While mechanisms underlying IFALD remain unclear, data in experimental SGS indicate a pivotal role for the microbiome and host TLR4 in driving IFALD. It is well known that the bowel's lymphatic vasculature is the route through which long chain fatty acids are absorbed as triglycerides into the body via large (~1 m) specialized lipoproteins called chylomicrons that are packaged and secreted by intestinal epithelial cells. It is less widely recognized that HDL trafficking from the intestine also serves as an alternative means for cholesterol and fat soluble vitamins, such as tocopherol (vitamin E), to be absorbed. Typically, the HDL pathway of absorption is minor compared to the lymphatic-dependent chylomicron pathway. However, this may change in disease settings. Moreover, it is not known how HDL enters the host during absorption, but data strongly suggest that it travels via a lymphatic-independent route, perhaps via the portal venous route. If so, HDL may serve as a key alternative vehicle for fat absorption during times of impaired lymphatic transport. Because the liver receives the majority of its blood supply from the portal vein rather than the hepatic artery, the cargo in the portal vein would be expected to strongly impact liver physiology. Besides carrying fat-soluble nutrients, HDL and other lipoproteins are major vehicles for transport of microbial lipids like the TLR4 ligand lipopolysaccharide (LPS). Our preliminary data indicate that during SGS, LPS is shuttled to a greater extent to the portal vein than to lymph. We hypothesize that this shuttling occurs on HDL and drives TLR4-dependent IFALD in SGS. If so, then a long term goal may be to route it back to chylomicrons and a functional lymphatic network to protect the liver. To test the hypothesis that intestinal HDL bypasses lymphatics to enter the portal vein and carry LPS to the liver to promote IFALD, we will utilize an experimental model of SGS in mice to address (i) whether HDL normally bypasses lymphatics to mobilize fat-soluble nutrients and microbial lipids to the portal blood (aim 1), (ii) whether this pathway is elevated in SGS because lymphatic integrity and transport is compromised (aim 2), and (iii) whether HDL is a crucial vehicle for LPS to traffic to the liver in SGS (aim 3).